STAT4-dependent and -independent T helper type-2 immunity mediates protection against Pneumocystis lung infection (P3304)

Abstract Although it is clear that the loss of CD4+ T cells is a predisposing factor for the development of Pneumocystis pneumonia, the protective mechanisms mediated by CD4+ T cells are not well understood. Augmented production of Th1-type cytokines in the lungs of IL-10-/- mice correlated with enhanced P. murina clearance, whereas neutralization of IL-17 in normal mice compromised fungal clearance, suggesting that Th1 and Th17 cells play an important role during infection. STAT4 is critical for optimal Th1 and Th17 development, therefore we investigated its role in P. murina host defense. Our data shows that STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and Balb/c mice 14 days after infection, but only Balb/c STAT4-/- mice were susceptible to P. murina infection. Th2 responses in the lungs of BL/6 STAT4-/- mice, but not Balb/c STAT4-/- mice, were intact 28 days after infection and correlated with elevated M2 macrophage polarization. Additionally, anti-P. murina class-switched antibodies were increased in BL/6 STAT4-/- mice, but not Balb/c STAT4-/- mice, as a result of hyper-Th2 responses in the draining lymph nodes. Supporting our experimental observations, we found that lower IL-4, IL-5 and IL-13 levels in plasma from HIV+ patients correlated with Pneumocystis colonization. Collectively, our data suggests that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis.